Principal Investigator/Program Director (Last, First, Middle): Margolskee, Robert F During the past few years my laboratory has explored the involvement of taste signaling elements in gastrointestinal (GI) chemosensation. In particular, how macronutrients in the gut lumen are sensed and in turn regulate hormone release from specific enteroendocrine cells of the gut. We have determined that the very same signaling elements that underlie taste detection/transduction also are expressed in specific subtypes of enteroendocrine cells, so-called taste cells of the gut. Moreover, these signaling proteins function in the gut cells to sense, in effect to taste, the dietary contents within the lumen of the gut. Chemosensory responses of these enteroendocrine cells include hormone release to promote the gut's digestive and metabolic functions. A striking example of the importance of taste signaling elements to GI chemosensation comes from the observation that ?-gustducin knockout mice do not secrete GLP-1 (Glucagon-Like Peptide 1) from their enteroendocrine cells in response to infusion of glucose into the gut lumen [unreadable] because of this defect these mice have dysfunctional regulation of their plasma insulin and glucose levels, leading them to a prediabetic condition. Quite recently we have observed that a number of hormones and signaling elements typically found in enteroendocrine cells of the gut are present also in a subset of taste cells, which we're calling lingual endocrine cells or endocrine taste cells. We hypothesize that in response to tastants these taste cells release GLP-1 and other hormones that have local (paracrine) and/or systemic effects relevant to taste, digestion and satiety. Further, we hypothesize that taste signaling mediated by gustducin, T1R3, Trpm5 and other taste transduction elements contributes importantly to the endocrine and paracrine responses of these lingual endocrine cells. Our preliminary data show that GLP-1, glucagon and PYY (peptide YY) are expressed in endocrine taste cells. In addition, we have found that glucose and sweeteners elicit release of GLP-1 from these taste cells. The experiments proposed here aim to further characterize the functions of these lingual endocrine cells. We have combined molecular, cellular, transgenic, physiological and pharmacological methods to determine: 1. which gut signaling molecules are expressed in lingual endocrine cells;2. which hormones are released from these endocrine taste cells in response to specific tastants;and 3. which taste signaling elements are involved in tastant-elicited hormone release from endocrine taste cells. This multidisciplinary approach has promise for providing significant new insights into the nature of cephalic phase responses regulating taste cell release of GLP-1 and other hormones to regulate gut functions. This proposal has medical relevance to appetite, satiety, diabetes and obesity. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Margolskee, Robert F The same signaling elements that underlie taste detection/transduction also are expressed in gut enteroendocrine cells, where they function to sense the dietary contents within the lumen of the gut. A number of hormones typically found in enteroendocrine cells of the gut are present also in a subset of taste cells, called lingual endocrine cells or endocrine taste cells. The experiments proposed to identify and functionally characterize these lingual endocrine cells have medical relevance to appetite, satiety, diabetes and obesity. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page